A Study to See if hENT1 Testing on Tumour Tissue Can Predict Response to Treatment With Gemcitabine Chemotherapy and if a Different Chemotherapy Called FOLFOX is Better Than Gemcitabine in Metastatic Pancreas Cancer

Summary:

Chemotherapy is often used to help shrink the cancer temporarily and may improve survival for
patients with incurable pancreas cancer that has spread to other organs. In Canada, the
gemcitabine chemotherapy is used to treat pancreas cancer that has spread. The combination of
oxaliplatin with other chemotherapies, including 5-fluorouracil, leucovorin, and irinotecan
has also been studied and has benefit for patients with advanced pancreas cancer. To date,
there is no test that can be done on a patient's tumour to tell if chemotherapy will work in
pancreatic cancer. Human equilibrative nucleoside transporter 1 (hENT1) has been shown to be
a possible predictor that gemcitabine may or may not work but this needs to be proven in a
randomized study where patients get treated with gemcitabine or a different kind of
chemotherapy while their tumours get tested for hENT1.
This study is being done because we want to prove that hENT1 can predict if gemcitabine will
work in advanced pancreas cancer and if it can, we also would like to show that a different
chemotherapy combination called FOLFOX (a combination of 5-fluorouracil, leucovorin, and
oxaliplatin) will be helpful for patients whose tumours don't have hENT1.

Trial Description

Primary Outcome:

The difference Progression Free Survival (PFS) between Gemcitabine and FOLFOX treated patients in hENT1 high and hENT1 low pancreatic adenocarcinoma.

Secondary Outcome:

The difference in overall response rate (ORR) between the two treatment arms.

The rate of disease control (DCR), defined as the sum of complete response rate (RR), partial RR, and stable disease between the two treatment arms.

The difference in overall survival (OS) between the two treatment arms.

Health-related quality of life (HRQL) parameters in patients with metastatic pancreas adenocarcinoma treated in both treatment arms.

Pre-clinical and retrospective clinical data indicates hENT1 may be a predictive and
prognostic biomarker for gemcitabine (Gem) efficacy. To ultimately prove its use as a
biomarker, a prospective randomized study with hENT1 stratification is required. This study
would provide the highest level of confidence, and would, if positive, vault Gem into the
select few anticancer agents for which a truly sensitive population can be rationally
treated. By this "molecular triage", the risk/benefit ratio of Gem therapy for pancreas
cancer (PC) could be meaningfully improved while also providing rationale for the use of a
different treatment regimen should tumours have low hENT1. The comparator arm of FOLFOX was
chosen because of the recent data showing impressive patient outcomes with the use of
oxaliplatin-based treatments.
This is a randomized, open-label, multicentre, phase III trial in which eligible patients
with metastatic pancreatic adenocarcinoma will be randomized between Gem and FOLFOX with
predefined upfront testing for hENT1. To be eligible, patients will have to have adequate
tissue available for hENT1 testing which the Cross Cancer Institute (CCI) will ensure prior
to treatment randomization. Patients will have their tumour sample tested for the expression
of hENT1. A blinded pathologist with expertise knowledge and experience with hENT1 staining
at the lead centre (CCI) will be responsible for pathologic hENT1 classification via IHC.
hENT1 IHC will be determined and scored as previously outlined.(1) Once hENT1 status has been
confirmed, patients will then be randomized 1:1 between Gem and FOLFOX. Patients will be
treated on study until disease progression, overwhelming toxicity, or patient withdrawal of
consent. Dose adjustments for one or more of the study drugs will be based on toxicities
encountered by individual patients. Specific dose-adjustment and treatment guidelines for
hematologic and non-hematologic toxicities including neutropenia, diarrhea, renal toxicity,
and neurotoxicity will be outlined in the protocol. Prior to enrolment, screening procedures
will document compliance with inclusion and exclusion criteria. The primary endpoint will be
determination of the difference in PFS in the two study arms, defined from the study start
date until either an increase in the sum of the products of the diameters of measurable
lesions by ≥ 20% bases on revised RECIST guidelines version 1.1 (2), the appearance of any
new lesion, or a deterioration in clinical status that is consistent with disease
progression. Secondary endpoints will be determination of the differences in overall response
rate (ORR), disease control rate (DCR), and overall survival (OS). Administered dose
intensity of Gem and FOLFOX will be reported. Health-related quality of life (HRQL) will be
assessed for the duration of active treatment on study.
Patient Population: The target population is patients with measurable metastatic
adenocarcinoma of the pancreas who have not been previously treated with systemic therapy for
their metastatic disease and who have tumour samples amenable to hENT1 testing. Fine needle
aspiration biopsies will not be permitted. Patients who have received prior chemotherapy
delivered as part of initial curative therapy (i.e. neoadjuvant, adjuvant, and/or
concurrently delivered with radiation and/or surgery) are permitted as long as that treatment
was completed at least 6 months prior to study start date. Patients may have received prior
radiation therapy or surgery ≥ 4 weeks before study entry and must have recovered from the toxic
effects from any prior therapy. Patients with locally advanced adenocarcinoma of the pancreas
will be excluded. Full inclusion and exclusion criteria are detailed in the protocol.
Study Objectives:
Primary Objective: To determine the difference PFS between Gem and FOLFOX treated patients in
hENT1 high and hENT1 low pancreatic adenocarcinoma.
Secondary Objectives: 1) To determine the difference in ORR between the two treatment arms;
2) To determine the rate of disease control, defined as the sum of complete response rate,
partial response rate, and stable disease between the two treatment arms; 3) To determine the
difference in OS between the two treatment arms; 4) To determine the differences in HRQL of
patients on the two treatment arms.
Exploratory Objectives: 1) To investigate the role of hCNT3 and its interaction with
hENT1-related patient outcomes. 2) To evaluate excision repair cross complementing 1 (ERCC1)
and microsatellite instability (MSI) in tumour samples, both of which are increasingly being
linked to efficacy in oxaliplatin-based therapy but for which information in PC is lacking.
Duration of Treatment: Treatment will continue until objective or symptomatic disease
progression, overwhelming toxicity, or patient withdrawal of consent. A patient may continue
to receive all or any combination of study drugs for as long as the investigator feels is
appropriate, but will be discontinued from study in case of:
1) Clinical and/or radiological documented disease progression (as determined by revised
RECIST 1.1 criteria).(2) All drugs will be discontinued and the patient removed from study;
2) Occurrence of unacceptable toxicity (this may be due to one or more drugs resulting in one
or more study drug discontinuation); if all three drugs are discontinued the patient will be
removed from study; 3) Failure to recover from hematologic and/or non-hematologic toxicity to
re-treatment level despite dosing interruption of up to 28 days (this may be due to one or
more study drugs resulting in one or more study drug discontinuation); if all drugs in
regimen are discontinued the patient will be removed from study; 4) Patient's request
(withdrawal of consent) or Investigator's recommendation (this may be one or more study
drugs); if all three study drugs are discontinued patient will be removed from study; 5)
Patient death (complete Serious Adverse Event Report for deaths occurring within 30 days
after last study drug dose OR for deaths occurring after 30 days, only if considered related
to study drug).
Efficacy Endpoints: Response assessments will be performed every 8 weeks, regardless of
treatment cycle. History, physical exam, laboratory work, imaging, ECOG performance status
(PS), will be required at each response assessment. PS will be measured using the ECOG
performance status scale. Tumour marker (CA19-9) may be followed at the discretion of the
investigator but should not be used in determination of disease response and are not a
requirement of the study. Tumour response will be evaluated according to the revised RECIST
criteria 1.1.(2) Symptomatic progression will be defined as new or worsening disease symptoms
deemed by the treating oncologist to incompatible with continuation of study medication or
the requirement for palliative radiation therapy or a fall in ECOG performance status to ≥ 3
deemed to be due to disease and not study treatment. Should symptomatic progression occur,
imaging to confirm progression is advised but if not possible due to performance status, the
study stop date will be recorded as the date of progression.
Safety: The NCI CTCAE (version 4.0) will be used to evaluate the clinical safety of the
treatment in this study. Subjects will be assessed for adverse events at each clinical visit
and as necessary throughout the study. Safety will be assessed via vital signs, physical
exams, laboratory tests (including hematologic, serum chemistry, and liver function testing),
and adverse event determination. Pregnant and nursing females will be excluded from
participation in the trial.